1. Field of the Invention
The invention relates to the inhibition of Calmodulin kinase II (CaMKII). More specifically, the CaMKII inhibition can treat or prevent structural heart disease, for example contractile dysfunction following a myocardial infarction, or dilated cardiomyopathy.
2. Background Art
Myocardial infarction is a major cause of significant disability and death in the United States and in many other countries around the world, and accounts for approximately ⅔ of all heart failure.7 
Several disease-initiating events (e.g. myocardial infarction, untreated hypertension, congenital mutations of contractile proteins) can result in a common heart disease phenotype that consists of dilation of the cardiac chambers, resulting in reduction in contractile function (i.e., a decrease in the fraction of total blood ejected from each chamber during systole) that leads to the clinical syndrome of heart failure.7 Dilated cardiomyopathy includes two distinct disease entities. Dilated cardiomyopathy, as used herein, includes ischemic cardiomyopathy which is a disease entity characterized by left ventricular dilation and reduced contractile function. This condition can result after myocardial infarction when the normal compensatory hypertrophy of surviving, non-infarcted myocardium is insufficient.7 “Dilated cardiomyopathy” can also include increased myocardial mass and reduced contractile function due to a genetic abnormality of myocardial proteins in the absence of myocardial infarction.7 A subject with dilated cardiomyopathy is a subject who has decreased cardiac contractility due to dilation of the ventricles. Thus, a subject with dilated cardiomyopathy and contractile dysfunction has different and more severe dysfunction than a subject in whom hypertrophy of surviving non-infarcted myocardium has compensated for infarcted myocardium. Further, a subject with dilated cardiomyopathy and contractile dysfunction has disease that is distinct from other cardiac conditions including abnormal relaxation (i.e., diastolic dysfunction and cardiac arrhythmia.
Available therapies for heart failure are insufficient, and new methods of treatment are needed. The heart responds to infarction by hypertrophy of surviving cardiac muscle in an attempt to maintain normal contraction. However, when the hypertrophy is insufficient to compensate, dilated cardiomyopathy and reduced contractile function result, leading to heart failure and death.19 Despite important advances in medical therapies for preventing cardiac dysfunction and heart failure after myocardial infarction,15 these problems remain a significant unsolved public health problem.
No pharmacological therapy for dilated cardiomyopathy is curative or satisfactory, and many patients die or, in selected cases, undergo heart transplantation. Presently available pharmacological therapies for reducing cardiac dysfunction and reducing mortality in patients with heart failure fall into three main categories: angiotensin-converting enzyme (ACE) inhibitors, beta adrenergic receptor (OAR) antagonists, and aldosterone antagonists. Despite reducing mortality, patients treated with these medicines remain at significantly increased risk for death compared to age-matched control patients without heart failure. ACE inhibitors,11 βAR antagonists4 and (at least one type of) aldosterone receptor antagonist12 can significantly reduce the incidence and extent of cardiac dysfunction and heart failure after myocardial infarction. Other available pharmacological therapies include nitroglycerin, diuretics, positive inotropic agents (cardiac stimulants), and brain natriuretic peptide (BNP). These latter agents can provide symptomatic relief, but are not associated with reduced mortality in heart failure patients.
ACE inhibitors are associated with cough in 10% of patients and can result in renal failure in the setting of bilateral renal artery stenosis or other severe kidney disease.7 βAR antagonists are associated with impotence and depression, and are contraindicated in patients with asthma; furthermore, patients may develop worsened heart failure, hypotension, bradycardia, heart block, and fatigue with initiation of βAR antagonists7 Aldosterone receptor antagonism causes significant hyperkalemia and painful gynecomastia in 10% of male patients.7,12 Agents without a demonstrated mortality benefit are also associated with problems; most notable is the consistent finding that many cardiac stimulants improve symptoms, but actually increase mortality,7 likely by triggering lethal cardiac arrhythmias. In contrast, CaMKII inhibition is now known to reduce cardiac arrhythmias in animal models,20,21 and so represents a novel approach to enhancing cardiac function without increasing arrhythmias. Presently available pharmacological therapies are ineffective and are limited by significant unwanted side effects, and so development of new therapies with improved efficacy and less severe side effects is an important public health goal.
Calmodulin kinase II is an enzyme that is present in heart and is activated when Ca2+ increases inside the heart cells, and binds to the Ca2+ binding protein calmodulin.3 CaMKII activity can increase in patients with severe cardiomyopathy, but CaMKII has never been linked to dilated cardiomyopathy or deterioration of contraction in heart failure.
The present invention provides methods of improving (increasing) contractile function of the myocardium to treat dilated cardiomyopathy and heart failure by inhibiting CaMKII. The present invention further provides mouse models of cardiac-targeted CaMKII inhibition by transgenic over expression of a selective CaMKII inhibitory peptide, AC3-I. Thus, the present AC3-I transgenic mouse is an important new tool to test for the effects of chronic CaMKII inhibition in cardiac disease.